Synthesis of 2-BMIDA 6,5-bicyclic heterocycles by Cu(i)/Pd(0)/Cu(II) cascade catalysis of 2-iodoaniline/phenols

Article abstract of DOI:10.1039/c6cc04554e

A one-pot cascade reaction for the synthesis of 2-BMIDA 6,5-bicyclic heterocycles has been developed using Cu(i)/Pd(0)/Cu(ii) catalysis. 2-Iodoanilines and phenols undergo a Cu(i)/Pd(0)-catalyzed Sonogashira reaction with ethynyl BMIDA followed by in situ Cu(ii)-catalyzed 5-endo-dig cyclization to generate heterocyclic scaffolds with a BMIDA functional group in the 2-position. The method provides efficient access to borylated indoles, benzofurans, and aza-derivatives, which can be difficult to access through alternative methods.

Full text of DOI:10.1039/c6cc04554e

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Synthesis of 2-BMIDA 6,5-bicyclic heterocycles by
Cu(I)/Pd(0)/Cu(II) cascade catalysis of 2-iodoaniline/phenols
Received 00th January 20xx,
Accepted 00th January 20xx
Ciaran P. Seath, Kirsty L. Wilson, Angus Campbell, Jenna M. Mowat, and Allan J. B. Watson*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A one-pot cascade reaction for the synthesis of 2-BMIDA 6,5- subsequent chemoselective crossꢀcoupling processes as well as
bicyclic heterocycles has been developed using Cu(I)/Pd(0)/Cu(II) their application as precursors toward the formation of
catalysis. 2-Iodoanilines and phenols undergo
a Cu(I)/Pd(0)- oxindoles and benzofuranones.
catalyzed Sonogashira reaction with ethynyl BMIDA followed by in
situ Cu(II)-catalyzed 5-endo-dig cyclization to generate
heterocyclic scaffolds with a BMIDA functional group in the 2-
position. The method provides efficient access to borylated
indoles, benzofurans, and aza-derivatives, which can be difficult to
access through alternative methods.
a) Previous work: Direct borylation of heterocycle
i) Lithiation
ii) Transition metal-catalysis
i) n-BuLi
Pd/Ir
Br/H
BPin
BPin
ii) B(OR)3, pinacol
B2Pin2
X
X
X
X
b) Previous work: Condensation reactions using alkyl- and acyl-BMIDA (Yudin)
i) Furans and pyrroles
BMIDA
BMIDA
X = NH: NH4OAc, AcOH, rt
O
Bicyclic heterocycles are valuable throughout synthetic and
medicinal chemistry due to their prevalence as the core scaffold
of many bioactive molecules.1 The utility of heterocyclic
building blocks in chemical synthesis can be greatly enhanced
by the addition of a reactive boron functional group. These
motifs enable relatively facile installation of additional
functionality via various wellꢀestablished chemistries including
the Suzuki–Miyaura and Chan–Evans–Lam reactions.2,3
Accordingly, methods for the preparation of borylated
heterocyclic scaffolds remain highly prized.
X = O: TFA, rt
R
H
X
O
R
ii) Fused aza-heterocycles
O
N
MeCN, Et3N, ꢀ
N
BMIDA
Br
Z
BMIDA
Z
c) This work: Synthesis of borylated fused heterocycles via cascade catalysis
I
BMIDA
CuI Pd0 CuII
X = NTs, O
BMIDA
X
XH
2-haloaniline
ethynyl BMIDA
• New C–C and C–X bond
• Borylated 2-position
or phenol
Typical methods for the formation of borylated heterocycles
involve the formation of a CꢀB bond via stoichiometric
metallation (Scheme 1a(i))4 or transition metalꢀcatalyzed
borylation using Pd5 or Ir6 catalysts (Scheme 1a(ii)). Recent
Scheme 1 Approaches towards borylated heterocycles.
The formation of indoles and benzofurans via the
advances from the Yudin group have exploited the stability of Sonogashira reaction of 2ꢀhaloanilines and phenols with
alkyl BMIDA reagents in condensation reactions, providing a alkynes, followed by in situ Cacchiꢀtype intramolecular
route to various borylated heterocycles but without the cyclization has been thoroughly investigated.10 We identified
formation of a CꢀB bond (Scheme 1b).7
that the use of a suitable borylated alkyne could enable the
Herein, we report the synthesis of 2ꢀborylated 6,5ꢀbicyclic same annulation but generate products that are borylated in the
heterocycles using Cu(I)/Pd(0)/Cu(II) cascade catalysis 2ꢀposition. Acetylynic BMIDA reagents have been used under
approach (Scheme 1c).8,9 This method enables the oneꢀpot, Rhꢀ and Auꢀcatalysis to effect similar annulation processes.11ꢀ13
modular preparation of 2ꢀborylated indoles and benzofurans, Accordingly, our study commenced with the reaction of ꢀtosyl
including azaꢀderivatives, using simple iodoanilines or 2ꢀiodoaniline ( ) with ethynyl BMIDA ( ). Initial experiments
a
N
1
3
iodophenols in conjunction with ethynyl BMIDA. In addition, based on literature reaction conditions10 led to good conversion
we demonstrate the utility of the generated products within to the Sonogashira product intermediate (not shown);14
however, the subsequent cyclization event was inefficient,
providing the desired product 4a in only 19% yield (entry 1).
Increasing the quantity of CuI led only to a small increase in
conversion to 4a (entry 2). Cu(OAc)2 is known to facilitate
similar 5ꢀendoꢀdig cyclizations15 and while addition of 50 mol
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% Cu(OAc)2 delivered a significant increase in conversion to provided an additional increase (entry 9) while lowering the
4a
,
we noted
a
3
considerable quantity of Glaser–Hay loading of Cuꢀcatalysts provided the most significant
(entry 3).16 However, following a survey of improvements to deliver 87% yield of 5a with minimal alkyne
homocoupling of
reaction conditions including catalyst loading, base, and homocoupling (Table 1, entry 10).
temperature, alkyne homocoupling could be mitigated,
With effective reaction conditions in place, we assessed the
delivering an efficient set of reaction conditions that produced generality of the process (Scheme 2).
4a in 83% yield (entry 4 – see Electronic Supporting
I
PdCl2(PPh3)2 (2 mol %), DMF
BMIDA
R
BMIDA
R
Information (ESI) for full details). The balance of base and
temperature was particularly crucial to avoid premature
hydrolysis of the generated heterocyclic BMIDA residue and
subsequent protodeboronation of the resulting heterocyclic
boronic acid. In addition, control reactions demonstrated the
requirement of all three catalysts – removal of either CuI or
Cu(OAc)2 led to diminished yields (entries 5 and 6). Removal
of Cu(OAc)2 gave effective Sonogashira crossꢀcoupling but
ineffective ring closure, providing 4a in only 22% yield (entry
5). Removal of CuI was found to hinder the Sonogashira step;
however, 4a was obtained in a moderate 63% yield. We believe
this was due to adventitious Cu(I) arising from either trace
levels in the unpurified Cu(OAc)2 or disproportionation of
Cu(II) to Cu(I).17
X = NTs: Conditions A
X = O: Conditions B
X
XH
1 or 2
3
4a-m, 5a-e
Conditions A (X = NTs): CuI (10 mol %), Cu(OAc)2 (30 mol %), K3PO4 (1 equiv), 30–55 °C
Conditions B (X = O): CuI (6 mol %), Cu(OAc)2 (10 mol %), K2CO3 (1.5 equiv), rt–60 °C
F3C
BMIDA
BMIDA
BMIDA
BMIDA
N
N
N
Cl
Ts
Ts
Ts
4a, 82%
4b, 87%
4c, 91%
Cl
F
NC
BMIDA
BMIDA
BMIDA
N
N
N
Ts
Ts
Ts
CO2Me
4e, 75%
4d, 87%
4f, 93%
Br
F3CO
O2N
BMIDA
BMIDA
N
N
N
Ts
Ts
Ts
4g, 91%
4h, 80%
4i, 97%
Table 1 Reaction development.a
O
I
BMIDA
BMIDA
PdCl2(PPh3)2 (2 mol %), DMF
MeO
N
BMIDA
BMIDA
BMIDA
N
N
N
Ts
Ts
conditions
N
X
XH
X = NTs, 1
X = O, 2
Ts
4j, 81%
4k, 79%
4l, 67%
3
X = NTs, 4a
X = O, 5a
O2N
F
entry
reaction conditions
CuI (20 mol %), Et3N, 60 °C
CuI (50 mol %), Et3N, 60 °C
CuI (50 mol %), Cu(OAc)2 (50 mol
%), Et3N, 60 °C
X
yield (%)b
19%
BMIDA
BMIDA
BMIDA
BMIDA
N
1
2
3
NTs
NTs
NTs
O
N
O
Ts
4m, 99%
5a, 83%
5b, 89%
31%
NO2
62%
N
TBDMSO
BMIDA
BMIDA
O
O
O
4
CuI (10 mol %), Cu(OAc)2 (30 mol
%), K3PO4, 30–55 °C
NTs
83%
5c, 82%
5d, 88%
5e, 91%
Scheme 2 Scope of the annulation process.
5
6
CuI (10 mol %), K3PO4, 30–55 °C
Cu(OAc)2 (30 mol %), K3PO4,
30–55 °C
NTs
NTs
22%
63%
The developed process was found to be generally high yielding
for indole (4a-m) and benzofuran (5a-e) substrates, including
7
8
CuI (10 mol %), Cu(OAc)2 (30 mol
%), K3PO4, 30–55 °C
O
O
O
O
32%
51%
62%
87%
various azaꢀderivatives (4k
reaction conditions, a wide range of standard functional groups
was tolerated, including esters (4e 4j), ethers (4h 5c), halides
4c 4d 4e 4g 5b), nitriles (4f), and nitro groups (4i 4m 5d).
In addition, the process was also found to be amenable on
preparatively useful (mmol) scale (Figure 1) and
chromatographic purification was often not required – products
could be isolated cleanly following aqueous workꢀup and
subsequent precipitation/filtration.18
, 4l, 4m, 5e). Due to the mild
CuI (10 mol %), Cu(OAc)2 (30 mol
%), K3PO4, rt–60 °C
,
,
(
,
,
,
,
,
,
9
CuI (10 mol %), Cu(OAc)2 (30 mol
%), K2CO3, rt–60 °C
10
CuI (6 mol %), Cu(OAc)2 (10 mol
%), K2CO3, rt–60 °C
a
1/2 (1 equiv, 0.25 mmol, 0.125 M), 3 (1.2 equiv, 0.3 mmol),
PdCl2(PPh3)2 (2 mol %), Cu cat. (see Table), base (see Table), DMF,
temp. (see Table), N2. b Determined by HPLC analysis using an internal
standard.
Br
O2N
BMIDA
BMIDA
BMIDA
N
N
N
N
Ts
Ts
4g, 89% (900 mg)
Ts
4m, 99% (700 mg)
4a, 81% (750 mg)
With effective conditions for substrate
our attention to the analogous benzofuran formation from 2ꢀ
iodophenol, . However, the preferred conditions for indole
1 established, we turned
Figure 1 Annulation reactions on 1.5-2.0 mmol scale. Values in
parentheses are isolated masses of material.
2
formation delivered only 32% yield of 5a, with the mass
balance consisting of unreacted starting material and
homocoupled alkyne (entry 7). Alteration of the temperature
profile improved conversion but Glaser–Hay coupling remained
problematic (entry 8). Modification of the base to K2CO3
Electrophileꢀchemoselective
allowed use of dihalide starting materials to furnish Brꢀ and Clꢀ
bearing products (4c 4e 4g), providing a handle for further
functionalisation via crossꢀcoupling processes. For example, 4g
participates in chemoselective Suzuki–Miyaura crossꢀcoupling
Sonogashira
crossꢀcoupling
,
,
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with retention of the BMIDA unit (Scheme 3a).11,19 The robust scaffolds that have significant potential for application,
BMIDA protecting group allows hydrogenation of nitro azaꢀ particularly within drug discovery.
We thank the Carnegie Trust for a PhD studentship (CPS) and
the EPSRC UK National Mass Spectrometry Facility at Swansea
University for analyses.
indole 4m to give the corresponding amino azaꢀindole
can undergo chemoselective Chan–Evans–Lam coupling to
generate products such as in excellent yield (Scheme 3b). As
7, which
8
7ꢀazaꢀindoles are valuable kinase hingeꢀbinders,20 the
developed method therefore provides expedient access to
desirable multiꢀfunctional intermediates that can be used for
exploration of this chemotype in kinase drug discovery.
Notes and references
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Scheme 3 Product utility with retention of BMIDA.
,
Importantly, the BMIDA unit of the products was amenable to
manipulation. Suzuki–Miyaura crossꢀcoupling was effective
under our previously developed, mild reaction conditions
(Scheme 4a);19,21 increased temperatures or imbalance in the
base/H2O stoichiometry led to considerable levels of
protodeboronation. Lastly, oxidation of the BMIDA unit of
both indole 4a and benzofuran 5a could be achieved using
Oxone®, via in situ preparation of the BF3K derivative,22,23 to
deliver oxindole 10 and benzofuranone 11 (Scheme 4b).
Oxindoles are also an important kinase hingeꢀbinding motif; the
developed process allows access to intermediates that can be
diverted to two different chemotypes and therefore gives a new
approach to diversityꢀoriented synthesis within kinase drug
discovery.24
c
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e
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Scheme 4 Manipulation of the BMIDA unit.
b
c
In summary, we have developed a oneꢀpot tandem reaction for
the synthesis of borylated heterocycles from simple and readily
d
available
starting
materials.
Synthetically
valuable
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functionalized 2ꢀBMIDAꢀsubstituted indoles and benzofurans,
as well as azaꢀderivatives, are generated using the described
chemoselective Cu(I)/Pd(0)/Cu(II) catalysis method. Based on
the utility of the BMIDA unit, the products can be manipulated
in several ways to allow access to functionalised heterocyclic
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